Diclofenac formulations

ABSTRACT

The subject invention provides improved diclofenac gel formulations.

This is a continuation of application Ser. No. 14/413,922, filed Jan. 9,2015, which is a national stage application under 35 U.S.C. § 371 ofInternational Application No. PCT/EP2013/064123, filed on Jul. 4, 2013,which claims priority of European Patent Application No. 12176115.9filed Jul. 12, 2012; the contents of these applications are eachincorporated herein by reference.

FIELD OF THE INVENTION

The subject invention lies in the field of transdermal diclofenacformulations.

BACKGROUND OF THE INVENTION

Delivery of active agents across the skin or mucosal membrane isconvenient, pain-free, non-invasive and circumvents problems associatedwith the “first pass effect”. Such transdermal or topical drug deliveryis typically restricted to low molecular weight drugs and drugs withspecific lipophilic/hydrophilic balance able to penetrate the stratumcorneum.

Transdermal drug delivery systems enable chemical modification of thebarrier properties of the skin to effectively and efficiently permitpermeation thereof. Known drawbacks of transdermal delivery systems are,for example, the length of time needed for permeation, a frequent dosingregimen, and the volume size of a transdermal composition needed totransdermally deliver a sufficient therapeutic amount of the activeagent.

Diclofenac (2-(2,6-dichloranilino) phenylacetic acid) is a non-steroidalanti-inflammatory drug (NSAID) used to reduce inflammation and, as ananalgesic, to reduce pain. It is available in sodium, potassium,epolamine or diethylamine salt form in numerous dosage forms (oraltablet, oral syrup, topical gel, cataplasm, ophthalmic drop,suppository, etc.).

An example of a well-known transdermal diclofenac formulation isVoltaren® Gel 1% which comprises 1% diclofenac sodium. Voltaren® isindicated in the USA for the relief of the pain due to osteoarthritis ofjoints amenable to topical treatment, such as the knees and the hands.Up to 4 g of Voltaren® gel can be applied to lower extremities(including the knees, the ankles, and the feet) 4 times daily so that upto not more than 16 g daily of Voltaren® Gel 1% is applied to any singlejoint of the lower extremities. Up to 2 g of Voltaren® Gel 1% can alsobe applied to the upper extremities (which include the elbows, thewrists and the hands) 4 times daily so that up to not more than 8 gdaily of Voltaren® Gel 1% is applied to any single joint of the upperextremities. Overall, the total dose of Voltaren® Gel 1% should notexceed 32 g per day over all affected joints. Neither the total amount(up to 32 g per day) nor the frequency of application (4 times a day)are satisfactory from a patient perspective.

U.S. Pat. No. 7,335,379 discloses formulations for transdermal ortransmucosal administration of active agents, such as diclofenac,containing an alkanol, a polyalcohol, a monoalkyl ether of diethyleneglycol and a fatty alcohol with a fatty alcohol content of up to 2%.

SUMMARY OF THE INVENTION

It is an object of the invention to provide improved diclofenacformulations with improved diclofenac delivery across the skin.

It is a further object of the invention to provide improved diclofenacformulations allowing a reduced frequency of administration.

It is a further object of the invention to provide improved diclofenacformulations to be used in the treatment of both localized and systemicconditions.

The subject invention provides a transdermal or transmucosal formulationcomprising:

-   -   at least 3% wt of diclofenac,    -   C₂ to C₄ alkanol,    -   polyalcohol, and    -   monoalkyl ether of diethylene glycol; and    -   at least 3% wt of a fatty alcohol.

The subject invention further provides a transdermal or transmucosalformulation comprising: 3% wt of diclofenac, 45.0% wt of ethanol, 20.0%wt of propylene glycol, 5.0% wt of diethylene glycol monoethyl ether and3% wt of myristyl alcohol.

The subject invention further provides a transdermal or transmucosalformulation comprising: 3% wt of diclofenac, 45.0% wt of ethanol, 20.0%wt of propylene glycol, 5.0% wt of diethylene glycol monoethyl ether, 3%wt of myristyl alcohol, 1.50% wt of hydroxypropyl cellulose, and water.

The subject invention further provides a method for administeringdiclofenac to a mammal in need thereof, said method comprisingtransdermally administering to the skin or a mucosal membrane of amammal a formulation of the invention.

The subject invention further provides a method for treating pain;post-traumatic inflammation of tendons, ligaments, muscles and/orjoints; localized forms of soft-tissue rheumatism; localized forms ofdegenerative rheumatism; inflammatory disorders; dysmenorrhea; actinickeratosis caused by over-exposure to sunlight; acute migraine; femalebreast cancer; pain associated with bony metastases; fever due tomalignant lymphogranulomatosis (Hodgkin's lymphoma); multi drugresistant E. coli; Shy-Drager syndrome; and diabetes mellitus, saidmethod comprising transdermally administering to the skin or a mucosalmembrane of a mammal a formulation of the invention.

The subject invention further provides a kit comprising at least onecontainer comprising a formulation of the invention, and instructionsfor use thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, embodiments will now be described, by way ofnon-limiting example only, with reference to the accompanying drawings,in which:

FIG. 1 shows a flow chart of the preparation of a diclofenac gelformulation of the invention.

FIG. 2 shows the absolute permeation profile (in μg/cm²) of Voltaren®and of diclofenac formulations A and B (see Example 2).

FIG. 3 shows the relative permeation profile (in %) of Voltaren® and ofdiclofenac formulations A and B (see Example 2).

FIG. 4 shows the absolute permeation profile (in μg/cm²) of diclofenacformulations C, D and E (see Example 3).

FIG. 5 shows the relative permeation profile (in %) of diclofenacformulations C, D and E (see Example 3).

FIG. 6 shows the relative permeation profile (in %) of diclofenacformulations F, G and H (see Example 4).

FIG. 7 shows the relative permeation profile (in %) of diclofenacformulations I, J and K (see Example 5).

FIG. 8 shows the relative permeation profile (in %) of diclofenacformulations L, M and N (see Example 6).

FIG. 9 shows the relative permeation profile (in %) of diclofenacformulations O, P and Q (see Example 7).

FIG. 10 shows the relative permeation profile (in %) of diclofenacformulations R, S and T (see Example 8).

DETAILED DESCRIPTION OF EMBODIMENTS

The subject invention provides a transdermal or transmucosal formulationcomprising:

-   -   at least 3% wt of diclofenac,    -   C₂ to C₄ alkanol,    -   polyalcohol, and    -   monoalkyl ether of diethylene glycol; and    -   at least 3% wt of a fatty alcohol.

In one embodiment, the transdermal or transmucosal formulation furthercomprises at least one of a gelling agent, an anti-oxidant, and asolvent or any combination thereof.

It should be noted that the selection of the types and amounts of thecomponents present in a formulation of the invention, other thandiclofenac, is based on several factors, including, among others:potential for skin permeation of diclofenac from a formulation of theinvention, ease of manufacturing, compatibility between the variouscomponents of a formulation of the invention, and stability of aformulation of the invention. It is furthermore noted that thecomponents of the permeation enhancing system as defined herein arepresent in an amount sufficient to provide permeation enhancement ofdiclofenac through dermal or mucosal surfaces.

Unless expressly specified otherwise, the term “comprising” is used inthe context of the present application to indicate that further membersmay optionally be present in addition to the members explicitlymentioned. It is, however, contemplated as a specific embodiment of thepresent invention that the term “comprising” encompasses the possibilityof no members being present other than the ones explicitly mentioned. Inother words, for the purpose of this specific embodiment, the term“comprising” is to be understood as having the meaning of “consistingof”.

The following detailed description discloses specific and/or preferredvariants of the individual features of the invention. The presentinvention also contemplates as encompassing, as particularly preferredembodiments of the invention, those embodiments which are obtained bycombining two or more of the specific and/or preferred variantsdescribed for two or more of the features of the present invention.

Unless expressly specified otherwise, all indications of relativeamounts in the present application are made on a weight/weight basis.Indications of relative amounts of a component characterized by ageneric term are intended to refer to the total amount of all specificvariants or members covered by said generic term. If a certain componentdefined by a generic term is specified to be present in a certainrelative amount or range of amount, and if an embodiment of theinvention further characterizes this component as comprising a specificvariant or member covered by the generic term, it is intended that othervariants or members covered by the generic term may be present only inan amount such that the total relative amount of all components coveredby the generic term does not exceed the specified relative amount.Preferably, in such case, no other variants or members covered by thegeneric term are present at all.

Generally, when referring to a formulation comprising “x % wt” of aningredient, such formulation should be understood to allow for apharmaceutically acceptable variation in the % wt of said ingredient of±10%. For example, when referring to a formulation comprising “3% wt ofdiclofenac”, such formulation should be understood to allow for apharmaceutically acceptable variation in the % wt of diclofenac of +10%,i.e. from 2.7% wt to 3.3% wt.

The terms “transdermal formulation” or “transmucosal formulation” shouldbe understood to encompass a formulation of the invention capable ofdelivering diclofenac to a mammal administered with said formulation bypermeating the diclofenac through the skin or mucosal tissue (ormembrane), said formulation being topically applied, penetrating intothe target tissues (e.g. the synovial fluids of the joints), andeventually entering into the bloodstream of said mammal.

“Transdermal delivery” as used herein should be understood to encompasstransdermal, percutaneous and transmucosal administration, i.e. deliveryby passage/permeation of a drug through the skin or mucosal tissue intothe bloodstream.

The term “skin” or “skin tissue” or “skin membrane” as used hereininterchangeably should be understood to encompass any dermal membrane(including any epidermis or dermis layer of a skin membrane), includingany hairy or glabrous cutaneous membrane.

The term “mucosa” or “mucosal tissue” or “mucosal membrane” as usedherein interchangeably should be understood to encompass any moistanatomical membrane or surface on a mammal that can be permeated withoutswallowing such as oral, buccal, auricular, vaginal, rectal, nasal orophthalmic surfaces.

The term “topical” or “topically” is used herein as referring to directcontact of a formulation of the invention with a surface area of amammal, including any portion of a skin membrane or mucosal membrane.

The term “mammal” as used herein should be understood to encompass anymammal. In one embodiment, the mammal is a human.

When referring to diclofenac, it should be understood to refer to anyone or more of the NSAID named 2-(2,6-dichloranilino) phenylacetic acid(CAS Registry Number 15307-86-5), its sodium salt, its potassium salt,its epolamine salt, its diethylamine salt, and/or any otherpharmaceutically acceptable salt thereof.

For example, in one embodiment, a transdermal or transmucosalformulation of the invention comprises 3% wt of diclofenac, C₂ to C₄alkanol, polyalcohol, monoalkyl ether of diethylene glycol and fattyalcohol. In another embodiment a transdermal or transmucosal formulationof the invention comprises 3% wt of diclofenac, C₂ to C₄ alkanol,polyalcohol, monoalkyl ether of diethylene glycol, fatty alcohol andgelling agent. In a further embodiment, a transdermal or transmucosalformulation of the invention comprises 3% wt of diclofenac, C₂ to C₄alkanol, polyalcohol, monoalkyl ether of diethylene glycol, fattyalcohol, gelling agent, and anti-oxidant. In yet another embodiment, atransdermal or transmucosal formulation of the invention comprises 3% wtof diclofenac, C₂ to C₄ alkanol, polyalcohol, monoalkyl ether ofdiethylene glycol, fatty alcohol, gelling agent, anti-oxidant andsolvent.

It is envisaged that a formulation of the invention comprises C₂-C₄alkanol in an amount of about 5-60% wt (e.g. about 5, 10, 15, 20, 25,30, 35, 40, 45, 50, 55, 60% wt), polyalcohol in an amount of about 1-30%wt (e.g. about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30% wt), monoalkyl etherof diethylene glycol in an amount of about 0.2-25% wt (e.g. about 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0,8.0, 9.0, 10, 15, 20, 25% wt), and fatty alcohol in an amount of about3-5% wt (e.g. 3.0, 3.5, 4.0, 4.5, 5.0% wt). A formulation of theinvention may further optionally comprise, e.g., gelling agent(s) in anamount of about 0.05-5% wt (e.g. about 0.05, 0.06, 0.07, 0.08, 0.09,0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4,4.5, 5% wt) and/or anti-oxidant(s) in an amount of about 0.025-0.2% wt(e.g. about 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065,0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1%, 0.2% wt).

A “permeation enhancing system” as used herein should be understood tocomprise C₂ to C₄ alkanol, polyalcohol, monoalkyl ether of diethyleneglycol, and fatty alcohol, which together qualitatively and/orquantitatively enhance the absorption and/or permeation of diclofenac ofa formulation of the invention through the skin or a mucosal membrane ofa mammal treated with said formulation (as compared with the transdermaldelivery of diclofenac without said permeation enhancing system).

The term “C₂ to C₄ alkanol” as used herein should be understood to meanone or more C₂ to C₄ alkanes substituted with a hydroxy group (—OH).

In one embodiment, an alkanol utilized by a formulation of the inventionis one or more selected from the group consisting of ethanol,isopropanol, n-propanol, butan-1-ol and butan-2-ol. In anotherembodiment, said alkanol is ethanol. In a further embodiment, saidalkanol is ethanol present in an amount of about 40.0-50.0% wt in aformulation of the invention. In a further embodiment, said alkanol isethanol present in an amount of about 45.0% wt in a formulation of theinvention.

In some embodiments, an alkanol (such as for example ethanol) is alsoutilized by a formulation of the invention as the primary solvent forthe diclofenac. The quantity of the alkanol should be sufficient to atleast fully solubilize the diclofenac. Additionally, alkanols, such asethanol, are known to be efficient skin permeation enhancers which actby extracting polar stratum corneum lipids and, consequently, increasepartitioning for numerous drug substances.

In some embodiments, a formulation of the invention comprises alkanol ina hydroalcoholic mixture with water.

In the context of the present invention, the term “polyalcohol” as usedherein should be understood to mean one or more of a C₂ to C₆ alkane orC₂ to C₆ alkene, substituted with two or more hydroxy groups.

In some embodiments, a polyalcohol comprised in a formulation of theinvention is one or more selected from the group consisting of ethyleneglycol, propylene glycol, butylene glycol, and hexylene glycol. In oneembodiment, a polyalcohol comprised in a formulation of the invention ispropylene glycol. In another embodiment, a formulation of the inventioncomprises propylene glycol in an amount of about 20.0% wt.

The term “monoalkyl ether of diethylene glycol” as used herein should beunderstood to mean one or more diethylene glycols substituted with a C₁to C₆ alkyl ether.

In one embodiment, monoalkyl ether of diethylene glycol comprised in aformulation of the invention is one or both of diethylene glycolmonoethyl ether (DOME) and diethylene glycol monomethyl ether (DGMM). Inanother embodiment, a formulation of the invention comprises diethyleneglycol monoethyl ether. In yet another embodiment, a formulation of theinvention comprises diethylene glycol monoethyl ether in an amount ofabout 5.0% wt.

The term “fatty alcohol” as used herein should be understood to meanfatty alcohols having a branched or linear carbon body having 12 or morecarbon atoms.

In one embodiment, the fatty alcohol comprised in a formulation of theinvention is one or more selected from the group consisting of: myristylalcohol, lauryl alcohol, oleyl alcohol, cetyl alcohol, and stearylalcohol. In one embodiment, the fatty alcohol comprised in a formulationof the invention is myristyl alcohol. In another embodiment, aformulation of the invention comprises myristyl alcohol in an amount ofabout 3% wt. In yet another embodiment, a formulation of the inventioncomprises myristyl alcohol in an amount of more than about 3% wt. In yetanother embodiment, a formulation of the invention comprises myristylalcohol in an amount of about 3-5% wt.

In another embodiment, the formulation of the invention may comprise afatty ester having a branched or linear acid moiety having 12 or morecarbon atoms or having a branched or linear alcohol moiety having 12 ormore carbon atoms.

The term “gelling agent” as used herein should be understood to mean anyagent capable of transforming the composition into a gel. A gellingagent used in a formulation of the invention can be one or more selectedfrom the group including: carbomer (also known as carboxyethylene orpolyacrylic acid) such as carbomer (CARBOPOL™) 980NF or 940 NF, 981 or941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 934P NF, 971P NF,974P NF, 71G NF, Ultrez 10 NF, Pemulen TR-1 NF or TR-2 NF and NoveonAA-1 USP, cellulose derivatives such as ethylcellulose (EC),hydroxypropylmethylcellulose (HPMC), ethylhydroxyethylcellulose (EHEC),carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC) (Kluceldifferent grades), hydroxyethylcellulose (HEC) (Natrosol grades), HPMCP55, and Methocel grades, natural gums such as arabic, xanthan, guargums, and alginates, polyvinylpyrrolidone derivatives such as Kollidongrades, polyoxyethylene-polyoxypropylene copolymers such as Lutrol Fgrades 68 and 127, chitosan, polyvinyl alcohols, pectins, and veegumgrades. A tertiary amine, such as triethanolamine, trolamine,tromethamine, aminomethyl propanol, diisopropanolamine, or diethylamine,can be included to thicken and neutralize the system.

In one embodiment, the gelling agent comprised in a formulation of theinvention is a carbomer. Carbomer relates to a class of homopolymers ofacrylic acid with a high molecular weight, which are cross-linked withany of several polyalcohol allyl ethers. Non-limiting examples ofcarbomers are carbomer 940, carbomer 971P, carbomer 973, carbomer 974P,carbomer 980NF, and carbomer C981 NF (wherein the digit indicates theaverage molecular weight of the polymer chains).

In one embodiment, the gelling agent comprised in a formulation of theinvention is hydroxypropylcellulose. In another embodiment, aformulation of the invention comprises hydroxypropylcellulose in anamount of about 1.50% wt.

The term “anti-oxidant” or “stabilizer” as used herein interchangeablyshould be understood to mean any substance capable of preventingoxidation or reactions promoted by oxygen, peroxides, or free radicalsin a formulation. An anti-oxidant usable in a formulation of theinvention can be one or more selected from the group including:tocopherol and derivatives, ascorbic acid and derivatives, butylatedhydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid,citric acid, propyl gallate, sodium metabisulfite, sodium bisulfite,sodium sulfite, edetate disodium, edetate trisodium, edetatetetrasodium, and derivatives thereof. In one embodiment, theanti-oxidant comprised in a formulation of the invention is sodiummetabisulfite. In another embodiment, the anti-oxidant comprised in aformulation of the invention is propyl gallate. In yet anotherembodiment, the anti-oxidant is edetate tetrasodium. In anotherembodiment, a formulation of the invention comprises sodiummetabisulfite in an amount of from about 0.025% wt to about 0.10% wt. Inyet another embodiment, a formulation of the invention comprises propylgallate in an amount of up to about 0.05% wt. In yet another embodiment,a formulation of the invention comprises edetate tetrasodium in anamount of up to about 0.05% wt. In yet another embodiment, a formulationof the invention comprises sodium metabisulfite in an amount of fromabout 0.025% wt to about 0.10% wt and propyl gallate in an amount of upto about 0.05% wt. In yet another embodiment, a formulation of theinvention comprises sodium metabisulfite in an amount of from about0.025% wt to about 0.10% wt and edetate tetrasodium in an amount of upto about 0.05% wt.

As used herein the term “solvent” may encompass any type of solventsuitable for use in a transdermal or transmucosal formulation of theinvention, as detailed herein above. In one embodiment, a solventcomprised in a formulation of the invention is water.

The subject invention provides a transdermal or transmucosal formulationcomprising: 3% wt of diclofenac, 45.0% wt of ethanol, 20.0% wt ofpropylene glycol, 5.0% wt of diethylene glycol monoethyl ether and 3% wtof myristyl alcohol.

The subject invention further provides a transdermal or transmucosalformulation comprising: 3% wt of diclofenac, 45.0% wt of ethanol, 20.0%wt of propylene glycol, 5.0% wt of diethylene glycol monoethyl ether, 3%wt of myristyl alcohol, 1.50% wt of hydroxypropyl cellulose, and water.

The subject invention thus provides an advanced transdermal permeationenhancing system, comprising a combination of volatile solvent (e.g.ethanol) and non-volatile cosolvents (e.g. propylene glycol and e.g.diethylene glycol monoethyl ether) and fatty alcohols (e.g. myristylalcohol), embedded in an aqueous gel matrix.

In some embodiments, a formulation of the invention further comprises atleast one of a buffering agent, moisturizing agent, humectant,surfactant, neutralizing agent, chelating agent, emollient, or buffer.

In some embodiments, a formulation of the invention is in the form of agel, lotion, cream, spray, aerosol, ointment, emulsion, suspension,liposomal system, lacquer, patch, bandage, buccal tablet, wafer,sublingual tablet, suppository, vaginal dosage form or occlusivedressing. In a particular embodiment, the formulation is a gel.

In other embodiments, a formulation of the invention is in the form ofat least one of the following: a clear (transparent) formulation, awater washable formulation, a cool-to-the-touch formulation, aquick-drying formulation, a spreadable formulation and a non-greasyformulation.

In some embodiments, said formulation is in the form of a gel. In otherembodiments, said formulation is in the form of a clear transparent gel.

In some embodiments, a formulation of the present invention is applieddirectly to the skin as, for example, a gel, an ointment, or a cream orindirectly through a patch, bandage, or other occlusive dressing.

A formulation of the invention may be applied once daily, or multipletimes per day depending upon the condition of the patient. In someembodiments, said formulation is adapted for a once, twice, three timesor four times daily transdermal or transmucosal administration.

The present invention further provides a method for administeringdiclofenac to a mammal in need thereof which comprises transdermallyadministering to the skin or a mucosal membrane of a mammal aformulation of the invention.

A formulation of the invention can be used for the treatment of bothlocalized or systemic disorders. In that regard, the invention providesa transdermal or transmucosal formulation of the invention for use inthe treatment of: pain (e.g. dental pain, mild to moderatepost-operative or post-traumatic pain, mild to moderate post-operativeor post-traumatic pain in presence of inflammation, menstrual pain,endometriosis, pain resulting from kidney stones and gallstones, chronicpain associated with cancer, chronic pain associated with cancer inpresence of inflammation); post-traumatic inflammation of tendons,ligaments, muscles and/or joints (e.g. due to sprains, strains, andbruises); localized forms of soft-tissue rheumatism (e.g.tendovaginitis, bursitis, shoulder-hand syndrome, and periarthropathy);localized forms of degenerative rheumatism (e.g. osteoarthrosis of theperipheral joints of the vertebral column); inflammatory disorders (e.g.arthritis, rheumatoid arthritis, polymyositis, dermatomyositis,osteoarthritis, temporomandibular joint disorders, spondylarthritis,ankylosing spondylitis, and gout attacks); dysmenorrhea; actinickeratosis caused by over-exposure to sunlight; acute migraine; femalebreast cancer; pain associated with bony metastases; fever due tomalignant lymphogranulomatosis (Hodgkin's lymphoma); multi drugresistant E. coli; Shy-Drager syndrome; and diabetes mellitus.

In one embodiment, the invention provides a transdermal or transmucosalformulation of the invention for use in the treatment of osteoarthritis.

A formulation of the invention can be administered in combination withother treatments.

In a further aspect, the invention provides a kit comprising at leastone container comprising a formulation of the invention, andinstructions for use thereof.

In some embodiments, a kit of the invention comprises a container whichis adapted for dispensing a predetermined measured amount of saidformulation.

EXAMPLES

The invention is further described in the following examples, which arenot in any way intended to limit the scope of the inventions as claimed.

Example 1—Preparation of Diclofenac Gel Formulations

The 3% wt and 5% wt diclofenac formulations described in the Examplesbelow were prepared by methods known in the art, as schematically shownin FIG. 1. The preparation was carried out at bench scale (10 grams to1000 grams batch sizes) in amber glass bottles. Mixing andhomogenization was ensured either through magnetic stirring or by meansof marine propellers. The preparation was also carried out at largerbatch scale (e.g. 6 kg and beyond, e.g. 6-10 kg) in controlledenvironment under continuous vacuum and nitrogen blanketing withtemperature control into a stainless steel planetary mixer.

Example 2—In Vitro Skin Permeation Testing

Test Samples:

-   -   Voltaren® Gel 1% wt    -   Diclofenac sodium gel 3% wt containing 2% wt myristyl alcohol        (hereinafter Formulation A)    -   Diclofenac sodium gel 3% wt containing 3% wt myristyl alcohol        (hereinafter Formulation B)

The composition of these gel formulations is presented in Tables 1 and2.

TABLE 1 Voltaren ® Gel 1% COMPONENT Function % wt Diclofenac sodiumActive 1.00 Carbomer homopolymer Thickener ND Type C Cocoylcaprylocaprate Spreading ND (Cetiol LC) emollient Isopropyl alcoholSolvent ND Fragrance Odour masking ND agent Mineral Oil Solvent ND(liquid paraffin) Polyoxyl 20 Consistency ND cetostearyl ether enhancerPropylene glycol Solvent ND Strong ammonia Neutralizing ND solutionagent Water purified solvent qsf 100 ND — not disclosed in Voltaren ®leaflet.

TABLE 2 Formulations A and B A B COMPONENT Function % wt % wt Diclofenacsodium Active 3.0 3.0 Absolute Ethanol Solvent/skin perme- 45.0 45.0ation enhancer Propylene glycol Solvent/skin perme- 20.0 20.0 ationenhancer Diethylene glycol Solvent/skin 5.0 5.0 monoethyl etherpermeation enhancer Myristyl alcohol Skin permeation 2.0 3.0 enhancerHydroxypropyl- Gelling agent 1.50 1.50 cellulose (Thickener) Purifiedwater Solvent qs 100 qs 100

Testing was performed on frozen abdominal human skin (from one singledonor). The Voltaren® test formulation was tested in 4 replicates andthe Diclofenac test formulations were tested each in 5 replicates (total14 replicates, i.e. sliced skin samples). The thickness of each samplewas measured with a micrometer. The samples were consequently mounted onvertical glass Franz diffusion cells with a receptor compartment ofabout 7.0 mL, a donor compartment of 3.0 mL and a diffusion area of 1.77cm².

Phosphate buffered saline (PBS) with addition of 2% w/v oleth-20, i.e.polyoxyethylene (20) oleyl ether, at pH 7.4 was used as receptorsolution, maintained at 32.5° C. during the whole study and stirred at600 rpm. The study was performed using a Microette® Plus autosampler.

After 2 hours pre-incubation of the skin samples with the receptorsolution and integrity assessment by evaporimetry, about 10 mg of thediclofenac sodium gel formulations were applied with the tip of aplastic syringe plunger and gently spread over the 1.77 cm² diffusionsurface (thus reaching gel loading of 5.6 mg/cm²). Diffusion of the drugwas allowed in non-occluded conditions during 24 hours.

Receptor solution samples (1.0 mL) were automatically removed after 9hours, 14 hours, 19 hours and 24 hours (after 1.5 mL receptorcompartment priming). The samples were collected in 2 mL HPLC amberglass vials pre-sealed with septem crimp caps and pre-filled with 10 μLof a solution of trifluoroacetic (TFA) acid 10%. Then samples weretransferred into Eppendorf microtubes and centrifuged at 13500 rpmduring 5 minutes. Each supernatant (0.8 mL) was transferred in a 2 mLHPLC amber glass vial. Analysis of the samples was performed by HPLC.

The entire study was conducted at controlled room temperature (typicallybetween 20° C. and 25° C.

TABLE 3 Diclofenac Cumulative delivery after 24 hour permeation Meanabsolute Mean relative Steady-state delivery delivery flux FormulationReplicates [μg/cm² ± SD] [% ± SD] [μg/cm²h] Voltaren ® 4 1.19 ± 0.82 2.1 ± 1.41 0.06 ± 0.05 A 5 4.73 ± 3.45 2.85 ± 1.99 0.21 ± 0.12 B 5 7.11± 2.27 4.29 ± 1.32 0.27 ± 0.10

Conclusion

Increasing the myristyl alcohol content in a 3% wt diclofenac sodium gelformulation from 2% wt to 3% wt (i.e. a 50% increase) led to a linear1.5-fold increase of mean cumulative diclofenac delivery after 24 hours(from 4.7 μg/cm² to 7.1 μg/cm² in absolute, or from 2.9% to 4.3% inrelative).

Example 3—In Vitro Skin Permeation Testing

Test Samples:

-   -   Diclofenac sodium gel 5% wt containing 3% wt myristyl alcohol        (hereinafter Formulation C)    -   Diclofenac sodium gel 5% wt containing 2% wt myristyl alcohol        (hereinafter Formulation D)    -   Diclofenac sodium gel 3% wt containing 2% wt myristyl alcohol        (hereinafter Formulation E).

The composition of these gel formulations is presented in Table 4.

TABLE 4 Formulutions C, D and E C D E COMPONENT Function % wt % wt % wtDiclofenac Sodium Active 5.0 5.0 3.0 Absolute Ethanol Solvent/skin 45.045.0 45.0 permeation enhancer Propylene glycol Solvent/skin 20.0 20.020.0 permeation enhancer Diethylene glycol Solvent/skin 5.0 5.0 5.0monoethyl ether permeation enhancer Myristyl alcohol Skin permeation 3.02.0 2.0 enhancer Hydroxypropylcellulose Gelling agent 1.5 1.5 1.5(Thickener) Purified water Solvent qs 100 qs 100 qs 100

Each test formulation was tested (essentially as described in Example 2)in six (6) replicates (6 different fresh pig ear skin donors). Overall,eighteen (18) full thickness samples were used.

TABLE 5 Diclofenac Cumulative delivery after 24 hour permeation Meanabsolute Mean relative Steady-state delivery delivery flux FormulationReplicates [μg/cm² ± SD] [% ± SD] [μg/cm²h] C 6 4.73 ± 3.82 1.79 ± 1.430.25 ± 0.17 D 6 3.14 ± 1.92 1.16 ± 0.70 0.18 ± 0.08 E 6 2.84 ± 1.52 1.72± 0.89 0.17 ± 0.08

Conclusion

In a diclofenac 5% gel formulation, increasing the myristyl alcoholcontent from 2% to 3% (i.e. a 50% increase) led also to a linear1.5-fold increase of mean cumulative diclofenac delivered through theskin after 24 hours (from 3.1 μg/cm² to 4.7 μg/cm² in absolute, or from1.2% to 1.8% in relative).

Example 4—In Vitro Skin Permeation Testing

Test Samples:

-   -   Diclofenac sodium gel 3% wt containing 3% wt myristyl alcohol        (hereinafter formulation F)    -   Diclofenac potassium gel 3.15% wt (equivalent to diclofenac        sodium 3% wt) containing 3% wt myristyl alcohol (hereinafter        formulation G)    -   Diclofenac epolamine gel 3.88% wt (equivalent to diclofenac        sodium 3% wt) containing 3% wt myristyl alcohol (hereinafter        formulation H).

The composition of these gel formulations is presented in Table 6.

TABLE 6 Formulations F, G and H F G H COMPONENT Function % wt % wt % wtDiclofenac Active 3.0 3.15 3.88 Absolute Ethanol Solvent/skin 45.0 45.045.0 permeation enhancer Propylene glycol Solvent/skin 20.0 20.0 20.0permeation enhancer Diethylene glycol Solvent/skin 5.0 5.0 5.0 monoethylether permeation enhancer Myristyl alcohol Skin permeation 3.0 3.0 3.0enhancer Hydroxypropylcellulose Gelling agent 1.5 1.5 1.5 (Thickener)Purified water Solvent qs 100 qs 100 qs 100

Each test formulation was tested (essentially as described in Example 2)in six (6) replicates (6 different fresh pig ear skin donors). Overall,eighteen (18) full thickness samples were used.

TABLE 7 Diclofenac Cumulative delivery after 24 hour permeation Meanabsolute Mean relative Steady-state delivery delivery flux FormulationReplicates [μg/cm² ± SD] [% ± SD] [μg/cm²h] F 6 3.39 ± 1.91 2.07 ± 1.290.15 ± 0.07 G 6 3.25 ± 0.72 1.99 ± 0.48 0.14 ± 0.04 H 6 5.18 ± 2.62 3.20± 1.59  0.25 ± 0.102

Each test formulation was again tested (essentially as described inExample 2) in six (6) replicates (6 different fresh pig ear skindonors). Overall, eighteen (18) full thickness samples were used.

TABLE 8 Diclofenac Cumulative delivery after 24 hour permeation Meanabsolute Mean relative Steady-state delivery delivery flux FormulationReplicates [μg/cm² ± SD] [% ± SD] [μg/cm²h] F 6 5.03 ± 3.56 3.05 ± 2.170.24 ± 0.15 G 6 3.44 ± 1.97 2.01 ± 1.12 0.18 ± 0.10 H 6 5.08 ± 4.33 3.06± 2.46 0.25 ± 0.13

TABLE 9 Compilation of Tables 7 and 8 Mean relative delivery FormulationReplicates [% ± SD] F 12 2.56 ± 1.78 G 12 2.57 ± 2.15 H 12 3.13 ± 1.98

Conclusion

Use of any one of three salts of diclofenac, i.e. diclofenac sodium,diclofenac potassium and diclofenac epolamine in the presence of 3% wtmyristyl alcohol resulted in similar diclofenac delivery through theskin after 24 hours.

Example 5—In Vitro Skin Permeation Testing

Test Samples:

-   -   Diclofenac sodium gel 3% wt containing 3% wt myristyl alcohol        (hereinafter formulation I)    -   Diclofenac sodium gel 3% wt containing 3% wt myristyl alcohol        and 0.1% sodium metabisulfite (hereinafter formulation J)    -   Diclofenac sodium gel 3% wt containing 3% wt myristyl alcohol,        0.05% metabisulfite and 0.05% propyl gallate (hereinafter        formulation K).

The composition of these gel formulations is presented in Table 10.

TABLE 10 Formulations I, J and K I J K COMPONENT Function % wt % wt % wtDiclofenac Active 3.0 3.0 3.0 Absolute Ethanol Solvent/skin 45.0 45.045.0 permeation enhancer Propylene glycol Solvent/skin 20.0 20.0 20.0permeation enhancer Diethylene glycol Solvent/skin 5.0 5.0 5.0 monoethylether permeation enhancer Myristyl alcohol Skin permeation 3.0 3.0 3.0enhancer Hydroxypropylcellulose Gelling agent 1.5 1.5 1.5 (Thickener)Sodium metabisulfite Anti-oxidant — 0.1 0.05 Propyl gallate Anti-oxidant— 0.05 Purified water Solvent qs 100 qs 100 qs 100

Each test formulation was again tested (essentially as described inExample 2) in six (6) replicates (6 different fresh pig ear skindonors). Overall, eighteen (18) full thickness samples were used.

TABLE 11 Diclofenac Cumulative delivery after 24 hour permeation Meanabsolute Mean relative Steady-state delivery delivery flux FormulationReplicates [μg/cm² ± SD] [% ± SD] [μg/cm²h] I 6 1.19 ± 0.53 0.75 ± 0.340.05 ± 0.02 J 6 1.77 ± 0.72 1.08 ± 0.46 0.09 ± 0.04 K 6 2.07 ± 1.96 1.28± 1.22 0.10 ± 0.09

Conclusion

0.1% sodium metabisulfite increases diclofenac delivery from 1.19 μg/cm²to 1.77 μg/cm²; a combination of 0.05% sodium metabisulfite and 0.05%propyl gallate increased diclofenac delivery to 2.07 μg/cm².

Thus, in the presence of anti-oxidant, diclofenac delivery is at leastequivalent to the delivery without anti-oxidant and even improved.

Example 6—In Vitro Skin Permeation Testing

Test Samples:

-   -   Diclofenac potassium gel 3.15% wt, equivalent to diclofenac        sodium 3% wt (hereinafter formulation L)    -   Diclofenac potassium gel 3.15% wt containing 2% wt myristyl        alcohol (hereinafter formulation M)    -   Diclofenac potassium gel 3.15% wt containing 3% wt myristyl        alcohol (hereinafter formulation N).

The composition of these gel formulations is presented in Table 12.

TABLE 12 Formulations L, M and N L M N COMPONENT Function % wt % wt % wtDiclofenac Active 3.15 3.15 3.15 Absolute Ethanol Solvent/skin 45.0 45.045.0 permeation enhancer Propylene glycol Solvent/skin 20.0 20.0 20.0permeation enhancer Diethylene glycol Solvent/skin 5.0 5.0 5.0 monoethylether permeation enhancer Myristyl alcohol Skin permeation — 2.0 3.0enhancer Hydroxypropylcellulose Gelling agent 1.5 1.5 1.5 (Thickener)Purified water Solvent qs 100 qs 100 qs 100

Each test formulation was tested (essentially as described in Example 2)in six (6) replicates (6 different fresh pig ear skin donors). Overall,eighteen (18) full thickness samples were used.

TABLE 13 Diclofenac Cumulative delivery after 24 hour permeation Meanabsolute Mean relative Steady-state delivery delivery flux FormulationReplicates [μg/cm² ± SD] [% ± SD] [μg/cm²h] L 6 0.83 ± 0.65 0.51 ± 0.410.05 ± 0.04 M 5 3.11 ± 1.45 1.92 ± 0.96 0.16 ± 0.05 N 6  4.7 ± 3.85 2.79± 2.23 0.22 ± 0.17

Conclusion

Formulation N, containing 3.15% diclofenac potassium together with 3%myristyl alcohol, had significantly higher diclofenac delivery.

Example 7—In Vitro Skin Permeation Testing

Test Samples:

-   -   Diclofenac sodium gel 3% wt containing 2.7% wt. myristyl alcohol        (hereinafter formulation O)    -   Diclofenac sodium gel 3% wt containing 3% wt myristyl alcohol        (hereinafter formulation P)    -   Diclofenac sodium gel 3% wt containing 3.3% wt myristyl alcohol        (hereinafter formulation Q).

The composition of these gel formulations is presented in Table 14.

TABLE 14 Formulations O, P and Q O P Q COMPONENT Function % wt % wt % wtDiclofenac Active 3.0 3.0 3.0 Absolute Ethanol Solvent/skin 40.5 45.049.5 permeation enhancer Propylene glycol Solvent skin 1 8.0 20.0 22.0permeation enhancer Diethylene glycol Solvent/skin 4.5 5.0 5.5 monoethylether permeation enhancer Myristyl alcohol Skin permeation 2.7 3.0 3.enhancer Hydroxypropylcellulose Gelling agent 1.5 1.5 1.5 (Thickener)Purified water Solvent qs 100 qs 100 qs 100

Each test formulation was tested (essentially as described in Example 2)in six (6) replicates (6 different fresh pig ear skin donors). Overall,eighteen (18) full thickness samples were used.

TABLE 15 Diclofenac Cumulative delivery after 24 hour permeation Meanabsolute Mean relative Steady-state delivery delivery flux FormulationReplicates [μg/cm² ± SD] [% ± SD] [μg/cm²h] O 6 4.16 ± 2.73 2.46 ± 1.6 0.21 ± 0.12 P 6 5.01 ± 4.67 3.11 ± 2.93 0.24 ± 0.18 Q 6 5.60 ± 2.92 3.48± 1.81 0.29 ± 0.14

Conclusion

Formulation O which contains 90% of target amounts of ethanol, propyleneglycol, diethylene glycol monoethyl ether and myristyl alcohol, led to astatistically insignificant decrease of cumulated diclofenac through theskin after 24 hours (from 3.11% to 2.46%).

Similarly, formulation Q which contained 110% of target amounts ofethanol, propylene glycol, diethylene glycol monoethyl ether andmyristyl alcohol, Led to a statistically insignificant increase ofcumulated diclofenac through the skin after 24 hours (from 3.11% to3.48%).

Similar observation were also made with respect to the steady state fluxwhich for formulation O led to a statistically insignificant decreasefrom 0.24 μg/cm²h to 0.21 μg/cm²h and for formulation Q led to astatistically insignificant increase from 0.24 μg/cm²h to 0.29 μg/cm²h.

Thus, variations within ±10% have a very limited impact on thepermeability of diclofenac through the skin.

Example 8—In Vitro Skin Permeation Testing

Test Samples:

-   -   Diclofenac sodium gel 3% wt containing 3% wt myristyl alcohol        and 1.35% hydroxypropyl cellulose (equivalent to 7967 cP)        (hereinafter formulation R)    -   Diclofenac sodium gel 3% wt containing 3% wt myristyl alcohol        and 1.5% hydroxypropyl cellulose (equivalent to 10617 cP)        (hereinafter formulation S)    -   Diclofenac sodium gel 3% wt containing 3% wt myristyl alcohol        and 1.65% hydroxypropyl cellulose (equivalent to 13817 cP)        (hereinafter formulation T).

The composition of these gel formulations is presented in Table 16.

TABLE 16 Formulations R, S and T R S T COMPONENT Function % wt % wt % wtDiclofenac Active 3.0 3.0 3.0 Absolute Ethanol Solvent/skin 45.0 45.045.0 permeation enhancer Propylene glycol Solvent/skin 20.0 20.0 20.0permeation enhancer Diethylene glycol Solvent/skin 5.0 5.0 5.0 monoethylether permeation enhancer Myristyl alcohol Skin permeation — 2.0 3.0enhancer Hydroxypropylcellulose Gelling agent 1.35 1.5 1.65 (Thickener)Purified water Solvent qs 100 qs 100 qs 100

Each test formulation was tested (essentially as described in Example 2)in six (6) replicates (6 different fresh pig ear skin donors). Overall,eighteen (18) full thickness samples were used.

TABLE 17 Diclofenac Cumulative delivery after 24 hour permeation Meanabsolute Mean relative Steady-state delivery delivery flux FormulationReplicates [μg/cm² ± SD] [% ± SD] [μg/cm²h] R 6 3.21 ± 1.63 1.93 ± 1.060.16 ± 0.08 S 5 3.88 ± 1.19 2.41 ± 0.72 0.19 ± 0.04 T 52 4.7 ± 0.59 1.68± 0.35 0.17 ± 0.02

Conclusion

The increase of viscosity from about 8000 cP (formulation R) to about14000 cP (formulation T) leads to a variation of diclofenac delivery ofnot more than 15% and of less than 10% of the steady-state flux.

Optimal delivery of diclofenac occurred at about 10000 cP.

The invention claimed is:
 1. A transdermal or transmucosal formulationcomprising: about 3% wt of diclofenac, about 45% wt of ethanol, about20% wt of propylene glycol, about 5% wt of diethylene glycol monoethylether, and about 3% wt of myristyl alcohol.
 2. A transdermal ortransmucosal formulation comprising: about 3% wt of diclofenac, about45% wt of ethanol, about 20% wt of propylene glycol, about 5% wt ofdiethylene glycol monoethyl ether, about 3% wt of myristyl alcohol,about 1% wt of hydroxypropyl cellulose, and water.
 3. The formulation ofclaim 1 or 2, wherein the formulation is in the form of a gel, lotion,cream, spray, aerosol, ointment, emulsion, suspension, liposomal system,lacquer, patch, bandage, buccal tablet, wafer, sublingual tablet,suppository, vaginal dosage form, or occlusive dressing.
 4. Theformulation of claim 1 or 2, wherein the formulation is in the form of agel.
 5. The formulation of claim 1 or 2, wherein the formulation isadapted for transdermal or transmucosal administration according to aschedule having a periodicity selected from once to four times dailydosing.
 6. A method for administering diclofenac to a mammal in needthereof, the method comprising transdermally administering to the skinor a mucosal membrane of a mammal a formulation comprising: about 3% wtof diclofenac, about 45% wt of ethanol, about 20% wt of propyleneglycol, about 5% wt of diethylene glycol monoethyl ether, and about 3%wt of myristyl alcohol.
 7. A method for treating pain; post-traumaticinflammation of tendons, ligaments, muscles, and joints; localized formsof soft-tissue rheumatism; localized forms of degenerative rheumatism;inflammatory disorders; dysmenorrhea; actinic keratosis caused byover-exposure to sunlight; acute migraine; female breast cancer; painassociated with bony metastases; fever due to malignantlymphogranulomatosis (Hodgkin's lymphoma); multi drug resistant E. coli;Shy-Drager syndrome; and diabetes mellitus, said method comprisingtransdermally administering to the skin or a mucosal membrane of amammal a formulation comprising: about 3% wt of diclofenac, about 45% wtof ethanol, about 20% wt of propylene glycol, about 5% wt of diethyleneglycol monoethyl ether, and about 3% wt of myristyl alcohol.
 8. Themethod according to claim 7, wherein the inflammatory disorder isosteoarthritis.
 9. The method according to claim 7, wherein theformulation is administered in combination with another treatment.
 10. Akit comprising at least one container comprising a formulationcomprising: about 3% wt of diclofenac, about 45% wt of ethanol, about20% wt of propylene glycol, about 5% wt of diethylene glycol monoethylether, and about 3% wt of myristyl alcohol and instructions for usethereof.
 11. The kit according to claim 10, wherein the container isadapted for dispensing a predetermined measured amount of theformulation.